title: The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration.
abstract: The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.
authors.affiliation: Urology Department, Sto António Hospital, Porto Hospital Centre, Porto, Portugal; ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal. Electronic address: avfraga@gmail.com.
authors.forename: Avelino
authors.initials: A
authors.lastname: Fraga
authors.affiliation: Molecular Oncology Group-CI, Portuguese Institute of Oncology, Porto, Portugal; Genetics Laboratory, Faculty of Medicine, University of Lisbon, Lisboa, Portugal; LPCC - Portuguese League Against Cancer (NRNorte), Porto, Portugal; Instituto Rocha Cabral, Lisboa, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribeiro
authors.affiliation: Urology Department, Sto António Hospital, Porto Hospital Centre, Porto, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Príncipe
authors.affiliation: Urology Department, D. Pedro V Military Hospital, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lobato
authors.affiliation: Urology Department, S. João Hospital, Porto, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Pina
authors.affiliation: Medical Oncology Department, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Joaquina
authors.initials: J
authors.lastname: Maurício
authors.affiliation: Molecular Oncology Group-CI, Portuguese Institute of Oncology, Porto, Portugal; LPCC - Portuguese League Against Cancer (NRNorte), Porto, Portugal.
authors.forename: Cátia
authors.initials: C
authors.lastname: Monteiro
authors.affiliation: Molecular Oncology Group-CI, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Sousa
authors.affiliation: Urology Department, Central Lisbon Hospital Centre, Lisboa, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Calais da Silva
authors.affiliation: ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
authors.affiliation: ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal; Molecular Oncology Group-CI, Portuguese Institute of Oncology, Porto, Portugal; LPCC - Portuguese League Against Cancer (NRNorte), Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
mesh_terms: D000368:Aged; D000483:Alleles; D000726:Androgen Antagonists / Q000627:therapeutic use*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D000726:Androgen Antagonists; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Androgen deprivation therapy; Hypoxia inducible factor 1 alpha; Metastasis; Prostate cancer; Single nucleotide polymorphism